4-(1, 2, 3, 4, tetrahydroisoquinolino)-2-butyn-1-ol



3,051,714 Patented Aug. 28, 1962 Free 3,051,714 4-(1,2,3,4, TETRAHYDROISOQUINOLINO)- Z-BUTYN-l-OL John H. Biel, Milwaukee, Wis, assignor to Lakeside Laboratories, Inc., Milwaukee, Wis., a corporation of Delaware No Drawing. Filed Feb. 6, 1958, Ser. No. 713,549

1 Claim. (Cl. 260-289) This invention relates to alkynols. More particularly, this invention is concerned with the production of novel cyclicaminoalkynols.

This application is a continuation-in-part application of my copending application Serial No. 620,165, filed November 5, 1956, now Patent No. 2,867,619, issued January 6, 1959.

According to this invention there are provided novel cyclicaminoalkynols of the formula wherein m and n are the same or difierent integers, especially from 1 through 5, and

is a cyclicamino group, such as morpholino, pyrrolidino, piperidino, 1,2,3,4-tetrahydroisoquinolino, t1,2,3,4-tetrahydroquinolino, isoindolino, 4-lower alkyl piperazino, indolino, theophyllino and phenothiazino, and quaternary salts and acid addition salts thereof.

These compounds may be produced, as the tertiary bases, by reacting an appropriate haloalkynol of the formula with an appropriate cyclic secondary amine of the formula to produce the cyclicaminoalkynol of the formula wherein X is a reactive halogen such as bromine or chlorine, and m, n and have the significance previously assigned.

Some haloalkynols which may be used in this process are 4chloro 2-butyn l-ol, 6-bromo 3 hexyn l-ol, 8- chloro-4-octyn-1-ol and 5-chloro-2-pentyn-1-ol.

Included within the group of cyclicamines that may be used in the process are morpholine, piperidine, pyrrolidine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, isoindoline, 4-methyl-piperazine, indoline, theophylline and phenothiazine.

The cyclicaminoalkynols may be produced by reacting the haloalkynol with an excess of the cyclicamine in an inert solvent such as benzene. The reaction mixture is cooled during the initial exothermic reaction. A secondary amine hydrohalide forms and is separated by filtration and the filtrate refluxed to complete the reaction. The product is recovered by fractionally distilling the clarified reaction mixture.

Some of the cyclic aminoalkynols so produced are 4- pyrrolidino-Z-butyn-l-ol, 4-morpholino-2-butyn-1-ol, 4-

2 piperidino-Z-butyn l -o1, 6-morpholino-3 -hexyn-1-ol, 7- piperidino-Z-heptyn-l-ol, 8-pyrrolidino-4-octyn-.1-ol, 4-

(1,2,3,4 tetrahydroisoquinolino) 2-butyn 1-01, 4-(N- methylpiperazino) 2-butyn 1-01, 6-(1,2,3,4 tetrahydroquinolino) 3-hexyn-1-ol, '8-isoindolino 2-octyn-1-ol, 5- phenothiazino-2-pentyn-l-ol, 7-pyrrolid-ino-3-heptyn-1-ol, 6-piperidino-3-hexyn-l-ol and the like.

Acid addition salts are produced by contacting such compounds with a suitable acid such as a mineral acid like sulfuric acid or hydrochloric acid, or an organic acid such as formic acid, citric acid, maleic acid or fumaric acid.

Quaternary ammonium salts of the cyclicaminoalkynols are formed by contacting such a tertiary amine with an alkylating agent, preferably in the presence of a suitable organic solvent. Alkylating agents such as lower alkyl halides, including methyl chloride, ethyl bromide, methyl bromide, alkylating agents like methyl and ethyl sulphate as well as aryl substituted alkylating agents like o-chlorobenzyl bromide, phenethyl chloride and phenylpropyl bromide are representative compounds which may be used to form quaternary ammonium salts of these tertiary bases.

The cyclicaminoalkynols are useful intermediates in the preparation of cyclicaminoalkynyl esters of N-substituted piperidine carboxylic acids which are useful hypotensive compounds as is shown in my copending application Serial No. 620,165, filed November 5, 1956, now Patent :No. 2,867,619, issued January 6, 1959. The cyclicaminoalkynols also form useful esters with penicillin. They may also be used to neutralize acids in various solutions. The cyclicaminoalkynols form esters with acids of many types. These compounds may be partially reduced to the corresponding double bond derivatives and fully reduced to the saturated compounds.

The following examples are presented to illustrate the preparation of specific cyclicaminoalkynols within the scope and contemplation of the invention.

EXAMPLE 1 4-Piperidin0-2-Butyn-1-Ol To a solution of 127.5 g. of piperidine (1.5 M) in 200 cc. of benzene is added, in dropwise fashion, a solution of 62.7 g. of 4-chloro-2-butyn-tl-ol (0.6 M) in cc. of benzene. The mixture is refluxed for 3 hours. The precipitated piperidine hydrochloride is filtered 01f, washed with benzene, and benzene removed from the combined filtrates by vacuum distillation through a v14" Vigreux column. The residue is distilled through a 5" Vigreux column; B.P. 102104 C. (0.45 mm.), N 1.5076, yield 71.7 g. (78.1%).

Analysis.Calcd. for C H ON: N, 9.14. Found: N, 9.55.

The hydrochloride salt melted at -143 C.

Analysis.-Calcd. for C9H16C1N0: Cl, 18.70. Found: Cl, 18.97.

EXAMPLE 2 4- (1,2,3,4-Tetrahydroisoquinoline) -2-Butyn-1-Ol Found:

' of morpholine hydrochloride.

EXAMPLE 3 4-(N-Methyl Piperazino)-2-Butyn-1-0l In a manner similar to Example 1' a solution of- 183.0

.g. of N-methyl piperazine (1.83 M) in 240 cc; of benzene is reacted with a solution of 76. g.of 4-chloro-2-butyn- .1-01 (0.73 .M) in 145 'cc; of benzene- The residue is distilled through a 5" Vigreux column; B.'P. 104106 C.

4-Morpho lino -2-Butyn-l-Ol.

Into a 500 cc. 3-neck round bottom flask equipped with stirrer, reflux condenser (CaCl tube), addition funnel, and heating mantle is placed a solution of 87.0 g. morpholine (1.0 M) in 135 cc. benzene. In a rapid dropwise fashion a solution of 41.8 g. 4-chloro-2-butyn- 1-ol (0.4 M) in 75 cc. benzene is added; a vigorous exothermic reaction occurs accompanied by separation The mixture is heated to reflux for 3 hrs. After cooling to roomatemperature, the crystalline morpholine hydrochloride is filtered ofi, washed well on the filter with benzene, and the combined benzene filtrates concentrated by vacuum distillation through a 14" column. The residue is subjected to vacuum distillation through a 5' column. The desired amino 4 alcohol distills as a viscous oil, B.P. 104106/0.-1 mm., N 1.5087, yield: 56.3 g. or 90.8% of theory.

Analysis.-Calcd. for C H O 'N: N, 9.03%. Found: N, 9.18%.

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended 'to' be included the scope of the appended claim.

What is claimed is:

4- (1,2,3,4-tetrahydroisoquinolino)-2butyn-1-o1.

References Cited in the file of this patent UNITED STATES PATENTS 2,613,208 Van Hook et a1. Oct. 7, 1952 2,769,008 Reppe Oct. 30, 1956 2,782,191 Reppe Feb. 19, 1957 2,867,619 B161 Jan. 6, 1959 FOREIGN PATENTS 7 1,024,773 Germany Feb. 20, 1958 OTHER REFERENCES Epsztein et 31.: Bull. Soc. Chim (France), 1953, pages 952-6.

Colonge et al.: Bull. Soc. Chim (France), 1955, pages 502-3.

Reppe et al.: Justus Liebigs Annalen der Chemie, Band 59 6, page 1955).

UNITED STATES PATENT OFFICE CERTIHQATE @F GQRREGHUN Patent N0P 3,O51 7l4 A t 28 19 2 John He Biel It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2 lines 42 and 61, and column 3 lines 3 and 14 in ihe eitles of Examples 1 to 4 for "01 each occurrence in italics read ol in italicse Signed and sealed this 18th day of December 1962s (SEAL) Attest:

ERNEST w. SWIDER DAVID LADD Attesfing Officer Commissioner of Patents 

